tbuckley/cabot-search huggingface dataset:
De novo EGFR T790M mutations in a community-based oncology practice.
Authors: Marilyn Elaine Holt, Amanda Misch, Smita K. Rao, Emma Sturgill, Carissa Jones, Daniel Schlauch, Daniel Luckett, David R. Spigel, Suzanne Fields Jones, Andrew Jacob McKenzie
Journal: Journal of Clinical Oncology (2022)

3146 Background: With the 2018 FDA approval of osimertinib for first-line treatment in EGFR-mutated lung cancers, the prevalence of acquired EGFR T790M mutations is expected to decrease, heightening the significance of de novo T790M mutations. Previous studies have reported a wide range of de novo T790M prevalence, and smaller retrospective studies have indicated that germline T790M may comprise the majority of de novo T790M mutations. Here, we assess the frequency of de novo T790M mutations in a community-based setting and report on germline T790M mutations occurring within this population. Methods: Patients with T790M-positive lung cancer were identified using Sarah Cannon’s clinicogenomics database containing information for patients treated within the Sarah Cannon research network. All T790M mutations were detected on tissue- and plasma-based NGS tests delivered as part of routine care. De novo and germline EGFR T790M status was determined via manual electronic health record chart review. When available, allele fraction and %cfDNA values were extracted from the structured NGS report and analyzed separately. Results: Of T790M-positive lung cancers with available pretreatment testing results, 36% (16/44) were confirmed to be T790M+ prior to EGFR TKI exposure; five of these patients received germline testing, and all five were confirmed to have originated in the germline. Two patients with germline T790M mutations detected on testing ordered by external providers were added to our de novo T790M+ patient analysis after chart review. Co-occurring EGFR mutations, including L858R, were detected in pre-TKI samples for 78% (14/18) of de novo T790M+ patients (Table). Co-occurring mutations in TP53, KRAS, PTEN, or RB1 were detected in pre-TKI samples of all patients without co-occurring EGFR mutations. EGFR C797S was observed after osimertinib treatment in one of four patients with post-TKI testing results. Of confirmed germline T790M+ cases with available allele frequencies, 100% (4/4) had allele fractions &gt;0.5 (tissue) and/or %cfDNA values &gt;50% (plasma). Average allele fraction and %cfDNA values were higher for de novo T790M mutations (allele fraction: 0.5 ± 0.2; %cfDNA: 40% ± 20%) than for acquired T790M mutations (allele fraction: 0.3 ± 0.2; %cfDNA: 2% ± 2%). Conclusions: Roughly one-third of T790M mutations detected in real-world settings occur before EGFR TKI exposure and may be associated with germline inheritance. Allele frequency may be a potential indicator of de novo T790M mutations in scenarios where pre-treatment data is not available. Future studies will investigate the impact of de novo T790M mutations on treatment response and evolution of resistance mechanisms in osimertinib-treated patients. [Table: see text]
Bioinspired nano-vaccine construction by antigen pre-degradation for boosting cancer personalized immunotherapy
Authors: Qiu-Ling Zhang, Sheng Hong, Xue Dong, Di-Wei Zheng, Jun-Long Liang, Xue-Feng Bai, Xia-Nan Wang, Zi-Yi Han, Xian-Zheng Zhang
Journal: Biomaterials (2022)
Factors associated with DCIS treatment patterns in a large cancer center network.
Authors: Hayeon Kim, Hong Wang, Emilia Diego, David Anthony Clump, Kenneth Smith, Margaret Q. Rosenzweig
Journal: Journal of Clinical Oncology (2022)

e18589 Background: There remains variability in management of DCIS, particularly with radiation therapy (RT) and hormone therapy (HT). Little is known about DCIS treatment patterns according to patient characteristics. We examined associations between patient characteristics, treating center location and DCIS therapy received. Methods: We performed a retrospective registry review of all patients diagnosed and treated with DCIS from 2018-2019, collected from the UPMC network, an NCI designated cancer center, serving western and central Pennsylvania. Demographics and administered treatments were compiled from cancer registry records. Descriptive statistics and logistic regression were used for analysis. Treatment centers throughout the network were dichotomized to academic (academic practice) or community (non-academic) sites, race was divided into two groups, Black and White/Other. Neighborhood deprivation index (NDI) was dichotomized to median level at &gt; = 59% vs. &lt; 59% and extremes &gt; = 75% vs. &lt; 75%. Results: A total of 941 patients treated for DCIS;29 patients were not eligible for surgery because of trial enrollment randomizing away from surgery. Of the remaining 912 patients, 506 patients were from academic sites and 406 patients from community sites. Median patient age was 63 years old (range: 24-90 years). There were no treatment differences noted for age, race, or NDI. For treatment, 80 patients refused recommended HT; 46 patients refused recommended RT. The likelihood of receiving RT was similar between academic and community sites (64.3% vs. 67.2%; p= 0.47). Of those having surgery, 25% had mastectomy (231 of 912), more likely at academic sites (29% vs. 21%; p= 0.0045). Among patients with lumpectomy, community patents had greater HT utilization than academic patients (82% vs. 68%; p &lt; 0.001), while ER status was not different. Conclusions: Within the UPMC network, variability in the management of DCIS did not differ based on age, race, or NDI. However, academic practice locations had higher levels of mastectomy, while greater HT utilization was observed in community sites. Further qualitative information is under examination from patients and clinicians to better understand how treatment decisions are framed and completed in the context of patient centered care for DCIS.
Dysregulated Th1 cells in lung squamous cell carcinoma.
Authors: Jiahui Wang, Qiuru Zhou, Cihui Yan, Zhenzhen Hui, Tao Wang, Liuqing Zheng, Shanshan Xiao, Jian Zhou, Yu Zhao, Zhe Wang, Yulin Ren, Hao Wang, Xiubao Ren
Journal: Journal of Clinical Oncology (2022)

e20566 Background: Lung squamous cell carcinoma (LUSC) is one of the most common subtypes of lung cancer which lacks of effective treatments compared to lung adenocarcinoma. The Th1 subset in CD4 + T cells plays an indispensable role in antitumor immune responses. However, there are few studies on Th1 cells in LUSC. Methods: Firstly, we used single-cell RNA-seq to analyze the gene expression in 8 LUSC patients’ tissues, including tumor tissues, paracancerous tissues, normal tissues, lymphoid tissues, pre-treatment blood samples and pre-operative blood samples. A total of qualified 44969 CD4 + T cells and 22971 Th1 candidate cells (Because STAT1, STAT4 and T-bet can promote IFN-γ expression. We define CD4 + T cells with one or more of above four indicators as Th1 candidate cells (Th1 CDD cells)) were identified. Then, we validated Th1 CDD cells and CD8 + T cells of tumor sites in 32 patients with LUSC by using multiplex immunofluorescence staining and immunohistochemistry. Finally, we used flow cytometry to detect the IFN-γ of CD4 + T cells in human PBMCs which were co-incubated with the supernatant derived from LUSC cell lines to simulate the tumor inhibitory microenvironment. Results: Single cell RNA-seq results showed IFN-γ + Th1 CDD cells only account for about 25.28% of the total Th1 CDD cells. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the differentially expressed genes (DEGs) between IFN-γ + Th1 CDD cells and IFN-γ - Th1 CDD cells demonstrated that the decreased level of IFN-γ expression was associated with ribosomes, antigen presentation, cell-to-cell interactions, apoptosis, endoplasmic reticulum stress (ER stress) and so on. According to multiplex immunofluorescence staining and immunohistochemistry, there was a positive correlation between the IFN-γ + STAT1 + T-bet + Th1 CDD cells and CD8 + T cells in tumor stromal compartment. Flow cytometry showed decreased level of IFN-γ in Th1 cells co-incubated with LUSC-derived supernatant. Conclusions: The function of Th1 CDD cells is suppressed in LUSC. In our study, we found that the decreased function of Th1 CDD cells is associated with ER stress by single cell RNA-seq, which requires further research. Overall, this may highlight a new target for the treatment of LUSC.
Unique characteristics and outcomes of therapy-related acute lymphoblastic leukemia following treatment for multiple myeloma
Authors: Ricardo D. Parrondo, Zaid Abdel Rahman, Michael G. Heckman, Mikolaj Wieczorek, Liuyan Jiang, Hassan B. Alkhateeb, Mark R. Litzow, Patricia Greipp, Taimur Sher, Leif Bergsagel, Rafael Fonseca, Vivek Roy, Angela Dispenzieri, Mohamed A. Kharfan-Dabaja, Hemant S. Murthy, Sikander Ailawadhi, James M. Foran
Journal: Blood Cancer Journal (2022)
3D Jones-maxtrix scanning of polycrystalline films of blood plasma in the diagnosis of pathological conditions of human organs.
Authors: Liliya Tryfonyuk, Alexandr Dubolazov, Yuriy Ushenko, Irina Soltys, Natalia Pavlukovich, Oleksandr Ushenko
Journal: Journal of Clinical Oncology (2022)

e15053 Background: This work is devoted to the development and experimental verification of a new method of three-dimensional matrix mapping of anisotropic properties of optically thin layers of polycrystalline films of blood plasma of biological tissues for express diagnostics and differentiation of histological sections of a prostate tumor. Methods: Biological samples. Three representative groups of polycrystalline blood plasma films were formed: 1 group consisted of blood plasma samples of polycrystalline adenoma; Group 2 consisted ofpolycrystalline adenocarcinoma, blood plasma samples are moderately differentiated (3+3 on the Gleason scale); Group 3 consisted ofpolycrystalline adenocarcinoma, blood plasma samples are poorly differentiated (4+4 on the Gleason scale). Results: The results obtained can be associated with changes in the ratio between the concentrations of albumin and globulin proteins in the blood plasma from patients with prostate tumors. It is known that malignant processes are accompanied by an increase in the concentration of optically active globulin molecules. Due to this, there is an increase in the magnitude and range of scatter in the magnitude of circular birefringence of samples of polycrystalline blood plasma films from patients with adenocarcinoma (3 + 3) and adenocarcinoma (4 + 4) in comparison with similar maps of blood plasma from patients with benign adenoma. On the contrary, due to a decrease in the concentration of albumin molecules, the values of linear birefringence of blood plasma films from patients with malignant prostate tumors decrease. Conclusions: The method of 3D Jones matrix mapping of blood plasma layers with digital holographic reconstruction of layered maps of linear and circular birefringence is analytically substantiated. The operational characteristics (sensitivity, specificity and balanced accuracy) that demonstrate the diagnostic power of 3D Jones matrix mapping of biological layers. The use of the algorithm for tomographic reproduction of linear birefringence maps provided high accuracy in differentiating benign and malignant conditions of the prostate tissue.[Table: see text]
Ivabradine rescues vascular abnormalities in a mouse model of duchenne muscular dystrophy
Authors: E Acar, M Kuruppu Appuhamilage, PL Szabo, S Trojanek, D Abraham, K Hilber, BK Podesser, A Kiss
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fonds zur Förderung der wissenschaftlichen Forschung Ivabradine rescues vascular abnormalities in a mouse model of muscular dystrophy Background Duchenne muscular dystrophy (DMD) is a rare genetic disorder that primarily affects boys, initiated by the absence of dystrophin and is mainly differentiated by skeletal muscle degeneration and cardiac dysfunction. However, recent studies have underlined the importance of vascular abnormalities such as augmented arterial stiffness and endothelial dysfunction in the progression of cardiac complications in DMD. Several pleiotropic effects of ivabradine have been identified, including the reduction of vascular complications in coronary artery and ischemic heart disease patients. Nevertheless, whether chronic ivabradine treatment could improve the vascular complications in DMD is largely unknown. Methods In this study, vascular abnormalities in both dystrophin and utrophin deficient (mdx-utr KO) mice were examined, a severe and progressive animal model of DMD. Mice (4-6 weeks old) were subjected to ivabradine (10 mg/kg/day in drinking water) or vehicle treatments for 3 to 4 weeks. At the end of the treatment, aorta and lung tissue were collected to assess the vascular reactivity by wire myograph and the activity of angiotensin-converting enzyme (ACE) activity was measured in lung tissue respectively. Results Comparable with DMD patients, mdx-utr KO mice also exhibit vascular abnormalities and cardiac fibrosis. Ivabradine-treated mice showed a significantly improved endothelium-dependent vasodilation (p&amp;lt;0.05) and decreased vascular stiffness compared to vehicle-treated animals (p&amp;lt;0.01). In addition, lung ACE activity was significantly reduced in the treated mice in comparison to the control group (p&amp;lt;0.01) indicating less activation in the renin-angiotensin-aldosterone system, which causative plays role in the progression of vascular and cardiac dysfunction. Conclusions In conclusion, our study shows for the first time the beneficial effects of chronic ivabradine treatment on the progression of cardiac vascular complications in DMD and this may present a novel therapeutic approach. Further studies are needed to clarify the underling signalling mechanisms.
Erdheim-Chester disease: An orbital MRI study.
Authors: Julien Haroche, Yoram Gueniche, Damien Galanaud, Fleur Cohen-Aubart, Didier Dormont, Théophile Rousseau, Jean-Philippe Spano, Zahir Amoura, Valerie Touitou, Natalia Shor
Journal: Journal of Clinical Oncology (2022)

e19085 Background: Erdheim-Chester disease (ECD) is a rare L-group histiocytosis. Orbital involvement is found in a third of cases, but few data are available concerning the radiological features of ECD-related orbital disease (ECD-ROD). Our aim was to characterize the initial radiological phenotype and outcome of patients with ECD-ROD. Methods: Initial and follow-up orbital MRI from the patients with histologically proven ECD at a national reference center were reviewed. Results: Pathological orbital findings were recorded for 45(33%) of the 137 patients included, with bilateral involvement in 38/45 (84%) cases. The mean age of these patients was 62 years (24-81) and 78% were men. Intraconal fat infiltration around the optic nerve sheath adjacent to the eye globe (52%), with intense gadolinium uptake and fibrous component was the most frequent phenotype described. Optic nerve signal abnormalities were observed in 47% of cases. Two patients presented bilateral homogeneous extraocular muscle enlargement suggestive of the myositis type of ECD-ROD. None had isolated dacryoadenitis. Only seven patients (15%) had normal brain MRI findings. ECD-associated paranasal sinus involvement and post-pituitary involvement were detected in 56% and 53% of patients respectively. A decrease/disappearance of the lesions was observed in 17/24(71%) of the patients undergoing late follow-ups. Interestingly, ECD-ROD only rarely (7/45(16%)) revealed the disease, with exophthalmos being the most frequently identified feature in this subgroup (3/45 (6%)). Conclusions: Even though ECD-ROD can be clinically silent, it constitutes a broad array of lesions often resulting in optic nerve signal abnormalities, the functional outcome of which remains to be established. ECD-ROD should thus be assessed initially and subsequently monitored by orbital MRI and ophthalmological follow-up.
ETMR-05. Single-cell transcriptomics of ETMR reveals developmental cellular programs and tumor-pericyte communications in the microenvironment
Authors: Flavia W de Faria, Carolin Walter, Marta Interlandi, Viktoria Melcher, Nicole Riedel, Monika Graf, Natalia Moreno, Melanie Schoof, Dörthe Holdhof, Christian Thomas, Michael C Frühwald, Bruno Maerkl, Ben Ho, Sarah Sandmann, Julian Varghese, Martin Ebinger, Martin Schuhmann, Aysegül Canak, Annie Huang, Ulrich Schüller, Thomas K Albert, Kornelius Kerl
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Embryonal tumors with multilayered rosettes (ETMR) are pediatric brain tumors bearing a grim prognosis, despite intensive multimodal therapeutic approaches. Insights into cellular heterogeneity and cellular communication of tumor cells with cells of the tumor microenvironment (TME), by applying single-cell (sc) techniques, potentially identify mechanisms of therapy resistance and target-directed treatment approaches. MATERIAL AND METHODS: To explore ETMR cell diversity, we used single-cell RNA sequencing (scRNA-seq) in human (n=2) and murine ETMR (transgenic mode; n=4) samples, spatial transcriptomics, 2D and 3D cultures (including co-cultures with TME cells), multiplex immunohistochemistry and drug screens. RESULTS: ETMR microenvironment is composed of tumor and non-tumor cell types. The ETMR malignant compartment harbour cells representing distinct transcriptional metaprograms, (NSC-like, NProg-like and Neuroblast-like), mirroring embryonic neurogenic cell states and fuelled by neurogenic pathways (WNT, SHH, Hippo). The ETMR TME is composed of oligodendrocyte and neuronal progenitor cells, neuroblasts, microglia, and pericytes. Tumor-specific ligand-receptor interaction analysis showed enrichment of intercellular communication between NProg-like ETMR cells and pericytes (PC). Functional network analyses reveal ETMR-PC interactions related to stem-cell signalling and extracellular matrix (ECM) organization, involving factors of the WNT, BMP, and CxCl12 networks. Results from ETMR-PC co-culture and spatial transcriptomics pointed to a pivotal role of pericytes in keeping ETMR in a germinal neurogenic state, enriched in stem-cell signalling. Drug screening considering cellular heterogeneity and cellular communication suggested novel therapeutic approaches. CONCLUSION: ETMR demonstrated diversity in the microenvironment, with enrichment of cell-cell communications with pericytes, supporting stem-cell signalling and interfering in the organization of the tumor extracellular matrix. Targeting ETMR-PC interactions might bring new opportunities for target-directed therapy.
DIPG-32. Paediatric histone-mutant diffuse midline glioma: real world outcomes from a low-middle income country (LMIC) setting
Authors: Tejpal Gupta, Abhishek Chatterjee, Archya Dasgupta, Akshay Mangaj, Sridhar Epari, Ayushi Sahay, Amit Choudhari, Aliasgar Moiyadi, Prakash Shetty, Girish Chinnaswamy
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Histone-mutant diffuse midline glioma (H3K27M) is a distinct high-grade central nervous system (CNS) tumor arising in the midline structures of the brain and/or spinal cord in children and young adults with dismal clinical outcomes. Real world data on this entity, particularly from the low-middle income countries (LMICs) is lacking. We report outcomes of pediatric histone-mutant diffuse midline gliomas treated between 2014-2021 at our comprehensive cancer centre in India. METHODS: Children (&amp;lt;16 years) with biopsy-proven diffuse midline glioma demonstrating histone mutation (H3K27M) on gene expression profiling were identified through electronic search of neuro-pathology database. Clinico-demographic characteristics, histo-molecular features, treatment details, and survival outcomes were retrieved retrospectively from institutional records. All children had undergone biopsy and occasionally debulking surgery prior to definitive radiotherapy (RT). Upfront temozolomide (TMZ) either concurrent and/or adjuvant was at the discretion of treating oncologist. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methods and expressed as point estimates with 95% confidence interval (CI). RESULTS: Median age of the study cohort (N=51) was 11 years (inter-quartile range 6-14 years) with no gender predilection. Metastatic disease (leptomeningeal dissemination, sub-ependymal spread, or distant brain involvement) was seen at presentation in 7 (13.7%) patients and at first progression after definitive RT in 10 (19.6%) patients. At a median follow up of 10.3 months, 1-year Kaplan-Meier estimates of PFS and OS were 21.5% (95%CI: 12.2-37.9%) and 45.6% (33.1-62%) yielding median PFS and OS of 7.8 months (95%CI: 5.6-11 months) and 11.3 months (95%CI: 9.4-14.9 months) respectively. CONCLUSIONS: We report aggressive biological course and dismal outcomes in pediatric histone-mutant diffuse midline gliomas (H3K27M) treated in a LMIC setting. High incidence of metastatic CNS failure in our cohort suggests a potential role for testing neuraxial irradiation and aggressive systemic therapy to improve survival.
Efficacy, safety and cost effectiveness of reduced-dose olanzapine versus aprepitant as a part of triple-antiemetic therapy in the prevention of chemotherapy induced nausea and vomiting.
Authors: Owais Mohammed, Narender kumar Thota
Journal: Journal of Clinical Oncology (2022)

e24078 Background: In Developing world, Olanzapine at a dose of 10mg is associated with excessive somnolence. Recently, reduced dose Olanzapine 5mg has been found to be equally effective with less sedation. Hence, we intended to conduct a study comparing the efficacy, safety, and cost effectiveness of reduced dose Olanzapine 5mg vs Aprepitant. Objectives: To compare Complete response (no emesis and no rescue therapy) rates between the two groups during three periods: 0 to 24 hours (acute), 25 to 120 hours (delayed), and 0 to 120 hours (overall) after chemotherapy. To compare nausea control rates in the acute, delayed, and overall periods. To evaluate potential adverse effects and compare cost effectiveness of Olanzapine, Aprepitant. Methods: All newly diagnosed cancer patients who were scheduled to receive highly emetogenic chemotherapy (either cisplatin at a dose ≥70 mg/ m2 body surface area, with or without other chemotherapeutic agents, or doxorubicin at a dose of 60 mg/m2 plus cyclophosphamide at a dose of 600 mg /m2) and had a European Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 were randomized 1:1 to receive triple anti emetic regimen comprising of 5HT3 antagonist (Palonosetron)+Steroid (Dexamethasone) + either NK1 antagonist (either Aprepitant 125mg on day 1, 80 mg on days 2, 3 or Fosapprepitant 150mg IV on day 1) or Olanzapine 5mg once daily on days 1-4). Number of Vomiting episodes, use of rescue therapy, nausea, other adverse effects were recorded. Results: A total of 154 patients were eligible for the study, 77 in each arm. The Complete response rates for Aprepitant and Olanzapine during the acute period were 79.22% and 81.81% respectively (p &gt; 0.05), during the delayed period were 74.02% and 70.12% respectively (p &gt; 0.05), during the overall period were 74.02% and 70.12% respectively (p &gt; 0.05). Nausea control rates for Aprepitant and Olanzapine during the acute period were 74.42% and 84.82% respectively (p &gt; 0.05), during the delayed period were 45.45% and 68.83% respectively (p &lt; 0.05), during the overall period were 45.45% and 68.83% respectively (p &lt; 0.05). Most common side effect in patients receiving Olanzapine was Somnolence which was observed in 12.98% patients (CTCAE Grade 2). Most common side effect in patients receiving Aprepitant was fatigue which was seen in 6.5% patients. A 4-day course of Olanzapine costs INR-20/- while a 3-day course of Aprepitant costs INR-1000/- and a single 150mg IV Fosapprepitant costs INR 2500/-. Conclusions: In the developing world, Olanzapine 5mg can be considered as an effective, safe, and a cheaper alternate to Aprepitant as a component of triple antiemetic regimen in the prevention of nausea and vomiting in patients receiving highly emetogenic chemotherapy.